glibenclamida contra sitagliptina..pdf

ORIGINAL RESEARCH

Comparison of Treatment with Sitagliptinor Sulfonylurea in Patients with Type 2 DiabetesMellitus and Mild Renal Impairment: A Post HocAnalysis of Clinical Trials

Elizabeth S. Ommen Lei Xu Edward A. ONeill Barry J. Goldstein

Keith D. Kaufman Samuel S. Engel

To view enhanced content go to www.diabetestherapy-open.comReceived: November 17, 2014 / Published online: January 30, 2015 The Author(s) 2015. This article is published with open access at Springerlink.com

ABSTRACT

Introduction: Impaired renal function is a

major complication of type 2 diabetes mellitus

(T2DM). Mild renal impairment is present in

38% of patients with T2DM and may impact

choice of antihyperglycemic agent.

Sulfonylureas and dipeptidyl peptidase-4 (DPP-

4) inhibitors are commonly used to treat

hyperglycemia in patients with T2DM and

renal impairment. Although in general

sulfonylurea use is associated with an

increased risk of hypoglycemia and weight

gain, while DPP-4 inhibitor use is associated

with a low risk of hypoglycemia, and is weight

neutral, the relative efficacy and tolerability of

these agents in patients with mild renal

impairment has not been evaluated.

Methods: In a post hoc analysis, data from

1,211 subjects with T2DM and mild renal

impairment (estimated glomerular filtration

rates of 60 to \90 mL/min/1.73 m2), whocompleted 25 or 30 weeks of one of three

double-blind clinical trials comparing the DPP-

4 inhibitor sitagliptin 100 mg/day with

sulfonylureas in titrated doses, were pooled.

The analysis compared change from baseline in

glycated hemoglobin (HbA1c), fasting plasma

glucose (FPG), body weight, incidence of

symptomatic hypoglycemia and the

percentages of subjects meeting a composite

endpoint of HbA1c decrease [0.5% withoutsymptomatic hypoglycemia or body weight

gain between sitagliptin and sulfonylurea

treatment groups.

Results: HbA1c and FPG decreased similarly with

sitagliptin or sulfonylurea. A lower incidence of

hypoglycemia was observed with sitagliptin.

Body weight decreased with sitagliptin but

increased with sulfonylurea. A greater

percentage of subjects treated with sitagliptin

(41.1%) than treated with sulfonylurea (16.9%)

Electronic supplementary material The onlineversion of this article (doi:10.1007/s13300-015-0098-y)contains supplementary material, which is available toauthorized users.

E. S. Ommen L. Xu E. A. ONeill B. J. Goldstein K. D. Kaufman S. S. EngelMerck & Co., Inc., Whitehouse Station, NJ, USA

E. S. Ommen (&)Clinical Research Department, Merck ResearchLaboratories, RY34-A214, Rahway, NJ 07065, USAe-mail: [email protected]

Present Address:B. J. GoldsteinCovance, Inc., Princeton, NJ, USA

Diabetes Ther (2015) 6:2940

DOI 10.1007/s13300-015-0098-y

achieved the composite endpoint of [0.5%HbA1c reduction with no symptomatic

hypoglycemia or body weight gain.

Conclusion: In this analysis of subjects with

T2DM and mild renal impairment, treatment

with sitagliptin provided glycemic efficacy

similar to sulfonylurea, with less hypoglycemia

and with body weight loss compared to body

weight gain seen with sulfonylurea.

Trial Registrations: ClinicalTrials.gov

#NCT00482079, #NCT00094770, #NCT00701090.

Keywords: DPP-4; Hypoglycemia; Incretins;

Renal impairment; Weight gain; Type 2

diabetes mellitus

INTRODUCTION

Among the many complications of type 2

diabetes mellitus (T2DM) arising from

prolonged hyperglycemia, as well as from

comorbid conditions such as hypertension, is

chronic kidney disease (CKD), which is present

in up to 40% of patients with T2DM [1].

Glycemic control reduces the incidence and

progression of microvascular complications of

diabetes [2, 3], but achieving adequate glycemic

control in patients with kidney disease can be

challenging. This challenge may be

underappreciated in patients with mild

impairment in kidney function, who account

for around 38% of patients with T2DM [4].

The routine reporting of estimated

glomerular filtration rate (eGFR) by clinical

laboratories, most commonly using the

Modification of Diet in Renal Disease (MDRD)

equation [5], allows clinicians a greater

awareness of patients level of renal function

and a greater recognition of even mild

impairment. The introduction of sodium

glucose co-transporter 2 inhibitors (SGLT2

inhibitors), a class of antihyperglycemic agent

with a renal-based mechanism of action, has

brought added emphasis to the importance of

renal function in choice of treatment for T2DM.

SGLT2 inhibitors demonstrate decreased

glycemic efficacy as renal function declines,

and this decrement begins in mild renal

impairment [6]. Mild renal impairment may be

relevant to metformin use as well: metformin is

recommended as first-line therapy in most

patients [7], but prescribing guidelines prohibit

its use at specific thresholds of serum creatinine

levels which correspond to only mild

reductions in eGFR in some patients [8].

In the Fourth National Health and Nutrition

Examination Survey (NHANES IV),

sulfonylureas were the most commonly used

antihyperglycemic agent in those with T2DM

and mild CKD, though this was before the

introduction of DPP4-inhibitors and other new

agents [1]. Sitagliptin is a DPP4-inhibitor which,

by preventing degradation of the incretins

glucagon-like peptide-1(GLP-1) and gastric

inhibitory polypeptide (GIP), stimulates

insulin release in a glucose-dependent manner

[9]. Sitagliptin is approved for patients with all

stages of CKD [10]; as sitagliptin is subject

primarily to renal elimination [11], dose

adjustment is recommended in patients with

moderate-to-severe renal impairment or on

dialysis so as to maintain drug exposure

similar to that obtained in patients with

normal renal function or only mild renal

impairment [12]. A substantial number of large

clinical studies have demonstrated sitagliptin to

be generally safe and well tolerated [13]. In

particular, because of the glucose-dependent

nature of the insulinotropic effect of sitagliptin,

the risk of hypoglycemia associated with use of

this therapy is very low, except when used in

combination with an agent that induces

glucose-independent insulin secretion [14].

30 Diabetes Ther (2015) 6:2940

The efficacy and safety of sitagliptin vs.

sulfonylurea in patients with T2DM and

moderate-to-severe CKD or end-stage renal

disease have been previously studied, showing

similar glycemic efficacy between the two

agents, and a lower risk of hypoglycemia and

less weight gain with sitagliptin treatment, but

otherwise generally similar safety and

tolerability [15, 16]. The current study is a post

hoc analysis of data pooled from 3 clinical trials,

comparing the efficacy, rates of hypoglycemia,

and changes in body weight in patients with

T2DM and mild renal impairment who were

randomized to either sitagliptin or a

sulfonylurea.

Subjects with mild renal impairment (eGFR

of C60 to\90 mL/min/1.73 m2) were identifiedfor this analysis using the MDRD equation to

estimate glomerular filtration rate (GFR) [17]. In

one of the 3 studies (referred to as Study 3), GFR

could be estimated by both the MDRD and the

Chronic Kidney Disease Epidemiology

Collaboration (CKD-epi) serum creatinine [18]

equations. The MDRD equation is imprecise

and systematically underestimates GFR at

higher levels of renal function [19]. Therefore,

to evaluate the accuracy of classification of

subject renal function by the MDRD equation

(the only method available for Studies 1 and 2),

baseline eGFR and renal function classification

were evaluated by both equations for all

subjects in Study 3 and compared.

METHODS

Data Sources

This was a post hoc analysis of pooled data from

subjects who participated in one of three

randomized, double-blind trials in which

sitagliptin was compared to a sulfonylurea,

had mild renal impairment (eGFR of C60 to

\90 mL/min/1.73 m2) at baseline asdetermined by the 4-variable MDRD equation

[17] (meeting eGFR criteria for mild [Stage 2]

CKD [20]), had glycated hemoglobin (HbA1c)

data at the analysis time points, and had no

major protocol violations. There was no rescue

therapy in these trials, as subjects with

persistent hyperglycemia were discontinued.

In Study 1 (Sitagliptin Protocol 010,

ClinicalTrials.gov#NCT00482079) [21], 743

subjects were 2176 years of age with baseline

HbA1c from 6.5 to \10.0% on diet alone; forStudy 2 (Sitagliptin Protocol 024,

ClinicalTrials.gov#NCT00094770) [22, 23],

1,172 subjects were 1878 years of age with

baseline HbA1c from 6.5 to 10.0% on

background metformin monotherapy; and for

Study 3 (Sitagliptin Protocol 803;

ClinicalTrials.gov#NCT00701090) [24], 1,034

subjects were C18 years of age with baseline

HbA1c from 6.5 to 9.0% on background

metformin monotherapy.

In Study 1, a dose-range finding study,

subjects were randomized in an equal ratio

among six treatment groups, of which two are

appropriate for inclusion in the present

analyses: the group randomized to sitagliptin

(100 mg per day administered as 50 mg twice

daily) and the group randomized to glipizide (in

titrated doses). The primary study duration was

12 weeks, subsequently extended to 104 weeks.

In Study 2, subjects were randomized 1:1 to

sitagliptin (100 mg per day) or glipizide (in

titrated doses). Study duration was 104 weeks

with the primary time point at Week 52. In

Study 3, subjects were randomized 1:1 to

sitagliptin (100 mg per day) or glimepiride (in

titrated doses). Study duration was 30 weeks. In

all 3 studies, sulfonylureas (or matching

placebo) were titrated based on self-performed

fingerstick glucose values. Up-titration was

Diabetes Ther (2015) 6:2940 31

withheld if the investigator considered that up-

titration would place the subject at

unacceptable risk for hypoglycemia, and

down-titration could be done at any time

during the study to prevent recurrent

hypoglycemic events. The mean standard

deviation dose of sulfonylurea achieved during

the analysis period in subjects included in this

analysis was 10.9 5.9 mg glipizide per day,

10.4 6.5 mg glipizide per day, and

2.0 1.4 mg glimepiride per day in studies 1,

2, and 3, respectively.

As indicated above, the three studies had

slight differences in their protocols, including

background therapy (i.e., diet/exercise or

metformin) and specific sulfonylurea

comparator. However, efficacy and safety in

both backgrounds are relevant to this analysis.

Therefore, because it is not expected that a

stable metformin background would impact

body weight or hypoglycemic events, and

because similar efficacy and side effect profiles

of the two second-generation sulfonylureas

were expected, data were combined from the

three studies in order to increase the power and

generalizability of the analysis.

All studies contributing data to the analysis

reported here were conducted in accordance

with principles of Good Clinical Practice and

were approved by the appropriate institutional

review boards and regulatory agencies. The

analysis in this article is based on previously

conducted studies, and does not involve any

new studies of human or animal subjects

performed by any of the authors.

Analysis Endpoints

Evaluation endpoints were changes from

baseline in HbA1c, fasting plasma glucose

(FPG), and body weight. The percentages of

subjects with HbA1c\7.0%, the percentages of

subjects with HbA1c decrease [0.5%, and thepercentages of subjects meeting a composite

endpoint of HbA1c decrease [0.5% with nosymptomatic hypoglycemia and no body

weight gain at the end of the study periods

were calculated. The percentages of subjects

reporting at least one adverse event (AE) of

symptomatic hypoglycemia, and the exposure-

adjusted event rate of reported AEs of

symptomatic hypoglycemia that occurred

during the analysis period were also

calculated. An AE of symptomatic

hypoglycemia was defined as any episode with

symptoms consistent with hypoglycemia; there

was no requirement for confirmation of

hypoglycemia by a measurement of blood

glucose levels. Severe hypoglycemia was

defined as an episode of hypoglycemia that

required assistance, either medical or non-

medical. Episodes with a markedly depressed

level of consciousness, a loss of consciousness,

or seizure were classified as having required

medical assistance, whether or not medical

assistance was obtained.

Statistical Analysis

In each study, the period evaluated began at

first dose of sitagliptin or sulfonylurea and

ended as close as possible to the final time

point for the study of shortest duration (Week

30 of Study 3).For Study 1, Week 25 data were

used for all endpoints. For Study 2, Week 30

data were used for HbA1c and FPG and Week 24

data for body weight. For Study 3, Week 30 data

were used for all endpoints. The incidence of

hypoglycemia was assessed through Week 25

(Study 1) or 30 (Studies 2 and 3). Since

treatment effects for both sitagliptin and

sulfonylurea generally plateau by 6 months,

these time points were considered to be

similar with regard to the endpoints of


interest. Further, any minor effects related to

the 5 week difference would be equally

balanced between the two treatment groups.

Results at the time point used for this analysis,

for each individual study for the full per-

protocol analysis population, are provided in

supplementary Table 1.

To be included in the analysis population,

subjects with appropriate eGFR at baseline had

to have completed Study 1 through Week 25 or

Studies 2 or 3 through Week 30, have a baseline

and end of analysis period HbA1c measurement,

and have no major protocol violations.

Analysis of covariance was used to compare

the treatment group changes from baseline for

the continuous endpoints, at time points

indicated. The model controlled for treatment,

study, and baseline value. The difference

between treatment groups in change from

baseline was assessed by testing the difference

in the least squares mean change from baseline.

Percentages and event rates were assessed using

the method of Miettinen & Nurminen [25],

stratified by study to calculate a nominal P value

for between-group differences. The event rate

was calculated as number of events divided by

total subject-years of exposure. The total

subject-years of exposure were calculated as

the sum, over all subjects, of the time from

the first dose to last dose of study medication

for the time period included in this analysis.

Using all available data from Study 3,

baseline eGFR and mild renal impairment

classification using the 4-variable MDRD

equation was compared with the baseline

values and classification obtained using the

CKD-epi creatinine equation, considering

CKD-epi eGFR to be the reference value. All

analyses were done using SAS (developed by SAS

Institute Inc., Cary, NC, USA.), version 9.3.

RESULTS

Of the 1,538 randomized subjects with mild

renal impairment across the three studies

(N = 774 treated with sitagliptin and N = 764

treated with a sulfonylurea), 1,211 (78.7%) met

the criteria for inclusion in this analysis

[N = 601 (77.6%) treated with sitagliptin and

N = 610 (79.8%) treated with a sulfonylurea].

Baseline demographic and anthropometric

characteristics of subjects in the two groups of

the pooled study cohort were similar (Table 1).

Table 1 Baseline demographic and anthropometriccharacteristics of randomized subjects in pooled studycohorts

Parameter Sitagliptin(N5 601)

Sulfonylurea(N5 610)

Age (years) 57.7 8.5 57.6 9.4

Male gender [n (%)] 326 (54.2) 357 (58.5)

Race [n (%)]

White 428 (71.2) 416 (68.2)

Asian 56 (9.3) 80 (13.1)

Black 18 (3.0) 21 (3.4)

Other 99 (16.5) 93 (15.2)

Body weight (kg) 85.8 16.6 86.4 16.8

Body mass index (kg/m2) 30.4 4.7 30.8 4.8

Estimated GFR [mL/min/

1.73 m2 (interquartile

range)]

75.9 7.6

(69.6, 81.6)

75.9 7.2

(70.4, 81.3)

HbA1c [% (range)] 7.6 0.8

(6.1 to

10.5)

7.6 0.9

(5.8 to

11.0)

FPG (mg/dL) 154.9 35.9 156.9 40.1

Duration of T2DM (years) 6.4 4.9 5.8 4.5

Data are expressed as mean standard deviation orfrequency [n (%)]GFR glomerular ltration rate, FPG fasting plasma glucose,T2DM type 2 diabetes mellitus. To convert FPG in mg/dLto mmol/L divide by 18


The mean age of subjects in the cohort was

57.7 years and their mean eGFR was 75.9 mL/

min/1.73 m2. The mean duration of T2DM in

the cohort was 6.1 years.

Changes from baseline in HbA1c were similar

between the sitagliptin- and the sulfonylurea-

treated groups (sitagliptin = -0.62%,

sulfonylurea = -0.68%; sitagliptin difference

from sulfonylurea group 0.06%, P = 0.104;

Fig. 1). The percentages of subjects with

HbA1c\7.0% or with [0.5% reduction inHbA1c were also similar between the two

groups (differences from sulfonylurea group

-4.7%, P = 0.092, Fig. 2 and 0.2%, P = 0.956,

Fig. 3, respectively). The FPG changes from

baseline observed with sitagliptin treatment

and with sulfonylurea treatment at Weeks 25

or 30 (Fig. 4) were similar (difference from

sulfonylurea group 1.6 mg/dL, P = 0.298).

A significantly smaller percentage of subjects

with mild renal impairment treated with

sitagliptin reported experiencing at least one

episode of symptomatic hypoglycemia

compared with subjects treated with a

sulfonylurea (6.5% with sitagliptin vs. 25.9%

with SU; P\0.001; Fig. 5). In addition, thereported number of symptomatic

hypoglycemia events in the sitagliptin group

Cha

nge

from

bas

elin

e H

bA1c

(L

S m

ean

% [9

5% C

I])

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Sitagliptin (N = 601) Sulfonylurea (N = 610)

-0.62-0.68

p = 0.104

Fig. 1 Glycated hemoglobin (HbA1c) change from base-line after 2530 weeks of treatment with sitagliptin or asulfonylurea. CI condence interval, LS least squares

Patie

nts

with

HbA

1c 0.5

% (

%)

0

20

40

60

80

100 Sitagliptin (n = 601) Sulfonylurea (n = 610)

56.9(n=342)

57.4(n=350)

p = 0.956

Fig. 3 Percentage of subjects with [0.5% reduction inglycated hemoglobin (HbA1c) after 2530 weeks of treat-ment with either sitagliptin or a sulfonylurea


during the analysis period (79) was lower

compared to the sulfonylurea group (609),

which, due to the similarity in treatment

durations, led to a significantly lower event

rate for symptomatic hypoglycemia in the

sitagliptin group compared with the

sulfonylurea group (Fig. 6). One subject in this

cohort, treated with a sulfonylurea, reported at

least one episode of severe hypoglycemia, while

no subject treated with sitagliptin reported an

event of severe hypoglycemia.

Mean body weight in the sulfonylurea group

increased while that in the sitagliptin group

decreased (Fig. 7), yielding a significant

between-group difference of -2.3 kilograms

(P\0.001).In the sitagliptin group, 41.1% of subjects

achieved the composite endpoint of an HbA1c

decrease of [0.5% with no reported event ofsymptomatic hypoglycemia and no increase in

body weight, a substantially larger percentage

than in the sulfonylurea group (between-group

difference 24.6%, P\0.001; Fig. 8).In Study 3, kidney function was evaluated by

both the standard MDRD equation and the

more recently validated CKD-epi equation. A

comparison of the results obtained by each

method suggests that if the CKD-epi equation

Patie

nts

with

at l

east

one

eve

nt

of s

ympt

omat

ic h

ypog

lyce

mia

(%)

0

10

20

30

40 Sitagliptin (N = 601) Sulfonylurea (N = 610)

6.5(n=39)

25.9(n=158)

p

was used to classify subjects for the current

pooled analysis, approximately 6.1% of subjects

in the pooled analysis would not have met

criteria for mild renal impairment (Table 2). Of

521 subjects classified by MDRD as having eGFR

of 60 to \90 mL/min/1.73 m2, 3 were classifiedby CKD-epi as having eGFR\60 mL/min/1.73 m2 and 29 were classified by CKD-epi as

having eGFR C 90 mL/min/1.73 m2.

DISCUSSION

Tight glycemic control has been shown to

reduce the risk of incident renal disease and to

slow progression in patients with established

renal disease [2, 3]. However, the rates of

optimal glycemic control may be lower in

patients with mild renal impairment compared

to patients without renal disease or with more

advanced disease. For example, in NHANES IV

and in a large cohort of individuals at high risk

for kidney disease, those individuals with T2DM

who had mild CKD had significantly worse

glycemic control compared to those who had

no CKD or who had moderate or severe CKD [1,

26, 27]. The reasons for these findings are

unclear, but may be due to lower levels of

medical engagement by patients with mild

renal impairment compared to those with

more advanced renal impairment, or lower

levels of vigilance by physicians when patients

have only mild disease. This may be exacerbated

by the practice of laboratories reporting MDRD-

derived eGFR calculations as C60 for all

individuals above that threshold, thus

providing a sense of reassurance that may not

be entirely warranted in patients with mild

renal impairment.

While the choice of antihyperglycemic

therapies for T2DM should take renal

functional status into account, clinicians may

not recognize mild renal impairment as a

category requiring such consideration. Several

clinical practice guidelines have recommended

the use of the CKD-epi equation for estimating

GFR, as the MDRD equation tends to

underestimate the true GFR in those with

higher GFR (e.g., mild renal impairment and

normal renal function) [28, 29]. However, in

routine clinical practice, the majority of clinical

laboratories continue to provide estimated GFR

values using the MDRD equation [5, 28].

In this post hoc analysis of subjects with

mild renal impairment, treatment with

sitagliptin or sulfonylureas provided similar

improvements in glycemic efficacy while there

was a significantly higher incidence of AEs of

symptomatic hypoglycemia with sulfonylurea

compared with sitagliptin. Sulfonylurea

treatment was also associated with weight gain

compared with weight loss with sitagliptin. The

results of this analysis show relative efficacy and

Table 2 The glomerular ltration rates of all subjects in Study 3 were estimated using both the 4-variable Modication ofDiet in Renal Disease (MDRD) equation and the Chronic Kidney Disease epidemiology collaboration (CKD-epi)creatinine equation

Subject eGFR classication

tolerability in subjects with mild renal

impairment identified by MDRD eGFR that is

comparable to that obtained in the overall

population from which these subjects were

selected [2124]. The overall findings of the

analysis reported herein are attributable to the

differing mechanisms of action of the two

classes of drugs evaluated. Sulfonylureas are

potent, glucose-independent insulin

secretagogues which act directly on pancreatic

beta cells [30]. Sulfonylureas stimulate a release

of insulin in a glucose-independent fashion,

making them effective antihyperglycemic

agents and also increasing the likelihood of

hypoglycemia. In contrast, the dipeptidyl

peptidase-4 (DPP-4) inhibitor sitagliptin acts

by stabilizing the DPP-4 substrates, GLP-1 and

GIP, both incretin hormones which act in a

glucose-dependent manner to increase the

secretion of insulin by beta cells [9].

DPP-4 inhibitors are generally considered to

be weight neutral, although the mild weight

loss observed in several studies of broad

populations of patients with T2DM [2224],

and in this analysis, may be related to

stabilization of GLP-1; activation of the GLP-1

receptor with the GLP-1 agonist liraglutide has

been shown to decrease body weight in patients

with T2DM [31]. In contrast, weight gain with

sulfonylureas is a known potential side effect

which may result from increased insulin levels

[32].

One limitation of this analysis is that AEs of

hypoglycemia were reported based on

symptoms and did not require measurement

of blood glucose level. Another potential

limitation is the use of the MDRD eGFR

equation to identify the population with mild

renal impairment for this analysis, as this

equation has been shown to be less accurate

at higher levels of renal function compared to

the CKD-epi serum creatinine equation [18].

However, the comparison performed using data

from all subjects in Study 3, in which both

equations could be used, showed that the rate

of possible misclassification was low, with

approximately 94% of patients being

accurately categorized using the MDRD

equation. Moreover, as many clinical

laboratories continue to use the MDRD

equation to calculate eGFR whenever serum

creatinine is performed [5, 28], the analysis

reported here is relevant in real-world clinical

practice settings.

Patients with diabetes and comorbid mild

CKD represent a population at increased risk for

progression to end-stage renal disease and for

cardiovascular events compared to patients

with diabetes without renal disease [33].

Management of hyperglycemia with

minimization of side effects such as

hypoglycemia and weight gain is clinically

desirable in all patients with diabetes, but may

be particularly important in patients with

diabetes and CKD, including mild CKD, given

the greater risks associated with this

combination of diseases. From the current

analysis, one can conclude that in patients

with T2DM and mild renal impairment

sitagliptin produces glycemic control similar to

sulfonylureas but with substantially less

hypoglycemia and without the weight gain

generally observed with sulfonylureas.

ACKNOWLEDGMENTS

This analysis and its publication, including

article processing fees, were funded by Merck

& Co., Inc., Whitehouse Station, NJ, USA. The

authors acknowledge the contributions of

Sheila Erespe at Merck& Co., Inc. for assistance

with submission of the article. All named

authors meet the ICMJE criteria for authorship


for this manuscript, take responsibility for the

integrity of the work as a whole, and have given

final approval to the version to be published.

Conflicts of interest. Elizabeth S. Ommen is

an employee of Merck Sharp & Dohme Corp., a

subsidiary of Merck & Co. Inc., Whitehouse

Station, NJ, and may own shares of Merck &

Co., Inc. stock or stock options. Lei Xu is an

employee of Merck Sharp &Dohme Corp., a

subsidiary of Merck & Co. Inc., Whitehouse

Station, NJ, and may own shares of Merck &

Co., Inc. stock or stock options. Edward A.

ONeill is an employee of Merck Sharp &

Dohme Corp., a subsidiary of Merck & Co.

Inc., Whitehouse Station, NJ, and may own

shares of Merck & Co., Inc. stock or stock

options. At time of writing Barry J. Goldstein

was an employee of Merck Sharp & Dohme

Corp., a subsidiary of Merck & Co. Inc.,

Whitehouse Station, NJ, and may own shares

of Merck & Co., Inc. stock or stock options.

Keith D. Kaufman is an employee of Merck

Sharp & Dohme Corp., a subsidiary of Merck &

Co. Inc., Whitehouse Station, NJ, and may own

shares of Merck & Co., Inc. stock or stock

options. Samuel S. Engel is an employee of

Merck Sharp & Dohme Corp., a subsidiary of

Merck & Co. Inc., Whitehouse Station, NJ, and

may own shares of Merck & Co., Inc. stock or

stock options.

Compliance with ethics guidelines. All

studies contributing data to the analysis

reported here were conducted in accordance

with principles of Good Clinical Practice and

were approved by the appropriate institutional

review boards and regulatory agencies. The

analysis in this article is based on previously

conducted studies, and does not involve any

new studies of human or animal subjects

performed by any of the authors.

Open Access. This article is distributed

under the terms of the Creative Commons

Attribution Noncommercial License which

permits any noncommercial use, distribution,

and reproduction in any medium, provided the

original author(s) and the source are credited.

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Comparison of Treatment with Sitagliptin or Sulfonylurea in Patients with Type 2 Diabetes Mellitus and Mild Renal Impairment: A Post Hoc Analysis of Clinical TrialsAbstractIntroductionMethodsResultsConclusion

IntroductionMethodsData SourcesAnalysis EndpointsStatistical Analysis

ResultsDiscussionAcknowledgmentsReferences

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